Project Summary Disease relapse and graft versus host disease (GVHD) continue to be major obstacles to improving outcomes for patients with hematologic malignancies undergoing allogeneic hematopoietic cell transplantation. Project 1 will develop and implement a series of novel clinical trials to address these issues in 3 Specific Aims. Aim 1 focuses on immune based strategies to prevent relapse for patients with myeloid malignancies undergoing HCT. These include clinical studies to examine the safety and impact of checkpoint blockade with ipilumumab administered early after allo-HCT in patients with myeloid malignancies at high risk of relapse based on genomic profiling prior to transplant. We will also complete a prospective phase 2 placebo controlled randomized trial of autologous leukemia cell vaccines genetically engineered to secrete GM-CSF (GVAX) administered prophylactically to patients with myeloid leukemias entering allo-HCT with active disease. A third trial will evaluate the impact of novel personal peptide vaccines after HCT designed to target leukemia-specific neoantigens and minor histocompatibility antigens based on genomic characterization of recipient leukemia cells compared with normal donor cells. Aim 2 focuses on patients who have relapsed despite allo-HCT and will test the efficacy and safety of a strategy that combines checkpoint blockade with adoptive cellular therapy manipulated to deplete regulatory T cells. Aim 3 will determine the safety and efficacy of combined IL-2 and ibrutinib therapy in patients with steroid-refractory chronic GVHD.